The long term goal of this proposal is to determine the cause of infantile polycystic kidney disease (PKD). In this laboratory, a new mouse model for autosomal recessive PKD has been found in the course of producing mutations with the drug, chlorambucil. This mutation has been preliminarily characterized as determining a severe infantile PKD; the gene has been called poly. Homozygous poly/poly mice die of extensive bilateral polycystic kidney disease at around 2 weeks of age. Most elements in the nephron appear to be affected. No other abnormalities have been noted. Heterozygous animals appear normal. This mutation is most likely due to a deletion of DNA since all other studied chlorambucil-induced mutations have been deletions. The following specific aims are proposed: (1) To characterize the PKD caused by the poly gene. Histological studies will be performed on both embryos and newborns. (2) To locate the chromosomal position of poly and determine if it is allelic to any known gene. Backcross and linkage crosses will be performed. DNA markers as well as morphological markers will be used for this purpose. More precise mapping will be performed once the gene is assigned to a particular chromosome. Allelism to nearby genes potentially affecting kidney function will be analyzed. (3) To walk into the gene by use of YAC libraries and positional mapping techniques. Approaches to this aim include the screening of YAC libraries, preparative pulsed-field gel electrophoresis, screening of cDNA kidney libraries, detection of CpG islands, zoo blots, Northern and Southern blotting, and direct positive selection of active kidney-expressed genes present on YACs. (4) To characterize the gene and determine its function. DNA sequencing and homology studies will be performed. Other animals mutants will also be screened for similar functional abnormalities. Finally, human families carrying a gene for infantile PKD will be studied by use of cross-hybridization techniques and Southern blot analysis.